Mechanisms of podocyte injury and implications for diabetic nephropathy

Federica Barutta, Stefania Bellini, Gabriella Gruden, Federica Barutta, Stefania Bellini, Gabriella Gruden

Abstract

Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy, and diabetic nephropathy (DN). Moreover, albuminuria is an important feature of all chronic kidney diseases (CKDs). Podocytes play a key role in maintaining the permselectivity of the glomerular filtration barrier (GFB) and injury of the podocyte, leading to foot process (FP) effacement and podocyte loss, the unifying underlying mechanism of proteinuric glomerulopathies. The metabolic insult of hyperglycemia is of paramount importance in the pathogenesis of DN, while insults leading to podocyte damage are poorly defined in other proteinuric glomerulopathies. However, shared mechanisms of podocyte damage have been identified. Herein, we will review the role of haemodynamic and oxidative stress, inflammation, lipotoxicity, endocannabinoid (EC) hypertone, and both mitochondrial and autophagic dysfunction in the pathogenesis of the podocyte damage, focussing particularly on their role in the pathogenesis of DN. Gaining a better insight into the mechanisms of podocyte injury may provide novel targets for treatment. Moreover, novel strategies for boosting podocyte repair may open the way to podocyte regenerative medicine.

Keywords: diabetic nephropathy; podocytes; proteinuria.

Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

© 2022 The Author(s).

Figures

Figure 1. Schematic representation of podocyte FPs
Figure 1. Schematic representation of podocyte FPs
The actin cytoskeleton of podocyte FPs is connected to both the SD, a specialised junction bridging the slit between FPs of neighbouring podocytes, and the GBM. Abbreviations: CD2AP, CD2-associated protein; GAG, glycosaminoglycan; LG, laminin G-like domain; MAGI, membrane-associated guanylate kinase; Nck, non-catalytic region of tyrosine kinase adaptor protein; PI3K, phosphoinositide 3 kinase; TRPC5/6, short transient receptor potential channel 5/6; ZO-1, zonula occludens-1.
Figure 2. Pathways of podocyte injury
Figure 2. Pathways of podocyte injury
The picture shows selected mechanisms leading to podocyte damage such as inflammation, oxidative stress, organelle dysfunction as detailed in the text. Abbreviations: ABCA1, ATP-binding cassette transporters A member 1; AF, autophagosome; AL, autolysosome; Ang-II, angiotensin-II; AT-1R, angiotensin II type 1 receptor; CB1R, endocannabinoid receptor of type 1; CB2R, endocannabinoid receptor of type 2; CCR2, C–C chemokine receptor 2; IL-1β, interleukin-1β; IL-1R, interleukin 1 receptor; MCP-1, monocyte chemoattractant protein 1; mtROS, mitochondrial reactive oxygen species; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; NOX4/5, NADPH oxidase 4/5; TNF-α, tumour necrosis factor-α; TNFR, tumour necrosis factor receptor.
Figure 3. TNT formation between podocytes
Figure 3. TNT formation between podocytes
(A) Representative image showing a TNT-like channel interconnecting two podocytes (magnification 630×, scale bar = 50 µm). Serial Z-stack images prove that the TNT does not adhere to the substrate. Colours represent the Z-depth (depth coding; red: bottom, blue: top). (B) Schematic representation of TNT-mediated mitochondrial transfer between podocytes.

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